| First Author | Cannon MV | Year | 2016 |
| Journal | Diabetologia | Volume | 59 |
| Issue | 3 | Pages | 634-43 |
| PubMed ID | 26684450 | Mgi Jnum | J:232590 |
| Mgi Id | MGI:5779603 | Doi | 10.1007/s00125-015-3827-x |
| Citation | Cannon MV, et al. (2016) LXRalpha improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes. Diabetologia 59(3):634-43 |
| abstractText | AIMS/HYPOTHESIS: Diabetic cardiomyopathy is a myocardial disease triggered by impaired insulin signalling, increased fatty acid uptake and diminished glucose utilisation. Liver X receptors (LXRs) are key transcriptional regulators of metabolic homeostasis. However, their effect in the diabetic heart is largely unknown. METHODS: We cloned murine Lxralpha (also known as Nr1h3) behind the alpha-myosin heavy chain (alphaMhc; also known as Myh6) promoter to create transgenic (Lxralpha-Tg) mice and transgene-negative littermates (wild-type [WT]). A mouse model of type 2 diabetes was induced by a high-fat diet (HFD, 60% energy from fat) over 16 weeks and compared with a low-fat diet (10% energy from fat). A mouse model of type 1 diabetes was induced via streptozotocin injection over 12 weeks. RESULTS: HFD manifested comparable increases in body weight, plasma triacylglycerol and insulin resistance per OGTT in Lxralpha-Tg and WT mice. HFD significantly increased left ventricular weight by 21% in WT hearts, but only by 5% in Lxralpha-Tg. To elucidate metabolic effects in the heart, microPET (positron emission tomography) imaging revealed that cardiac glucose uptake was increased by 1.4-fold in WT mice on an HFD, but further augmented by 1.7-fold in Lxralpha-Tg hearts, in part through 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and restoration of glucose transporter 4 (GLUT4). By contrast, streptozotocin-induced ablation of insulin signalling diminished cardiac glucose uptake levels and caused cardiac dysfunction, indicating that insulin may be important in LXRalpha-mediated glucose uptake. Chromatin immunoprecipitation assays identified natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as potential direct targets of cardiac LXRalpha overexpression. CONCLUSIONS/INTERPRETATION: Cardiac-specific LXRalpha overexpression ameliorates the progression of HFD-induced left ventricular hypertrophy in association with increased glucose reliance and natriuretic peptide signalling during the early phase of diabetic cardiomyopathy. These findings implicate a potential protective role for LXR in targeting metabolic disturbances underlying diabetes. |
